EP2014678B1 - Peptides KDR et vaccins les comportant - Google Patents

Peptides KDR et vaccins les comportant Download PDF

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Publication number
EP2014678B1
EP2014678B1 EP08018875A EP08018875A EP2014678B1 EP 2014678 B1 EP2014678 B1 EP 2014678B1 EP 08018875 A EP08018875 A EP 08018875A EP 08018875 A EP08018875 A EP 08018875A EP 2014678 B1 EP2014678 B1 EP 2014678B1
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Prior art keywords
peptides
cells
seq
hla
kdr
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Expired - Lifetime
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EP08018875A
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German (de)
English (en)
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EP2014678A3 (fr
EP2014678A2 (fr
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Hideaki Tahara
Satoshi Wada
Takuya Tsunoda
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Oncotherapy Science Inc
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Oncotherapy Science Inc
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Priority to EP10010175.7A priority Critical patent/EP2267023B1/fr
Priority to DK10010169.0T priority patent/DK2267021T3/en
Priority to EP10010176.5A priority patent/EP2270042B1/fr
Priority to EP10010172.4A priority patent/EP2261248B1/fr
Priority to EP10010173.2A priority patent/EP2261249B1/fr
Priority to DK10010174.0T priority patent/DK2267022T3/en
Priority to DK10010175.7T priority patent/DK2267023T3/en
Priority to EP10010170.8A priority patent/EP2270041B1/fr
Priority to DK10010173.2T priority patent/DK2261249T3/en
Priority to EP10010169.0A priority patent/EP2267021B1/fr
Priority to EP10010174.0A priority patent/EP2267022B1/fr
Priority to EP10010171A priority patent/EP2261247A3/fr
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Publication of EP2014678A2 publication Critical patent/EP2014678A2/fr
Publication of EP2014678A3 publication Critical patent/EP2014678A3/fr
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Publication of EP2014678B1 publication Critical patent/EP2014678B1/fr
Priority to CY20121100072T priority patent/CY1113379T1/el
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/4203—Receptors for growth factors
    • A61K40/4208—Vascular endothelial growth factor receptors [VEGFR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/50—Colon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/57—Skin; melanoma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • Tumor-rejection antigen genes have mainly been identified for malignant melanomas, and accordingly, cancer immunotherapies utilizing these genes are developed.
  • cancer vaccine therapy that induces tumor-specific CD8-positive T cells in vivo has received attention, and is being applied to various clinical applications.
  • the mechanism by which peptides consisting of approximately ten amino acid residues activate T cells via the Class I pathway, by the assistance of various costimulatory molecules, to induce tumor-specific cytotoxic T cells (CTLs) was also elucidated.
  • CTLs cytotoxic T cells
  • peptides in which the second amino acid from the N terminus is substituted with phenylalanine, tyrosine, methionine, or tryptophan, and in which the C-terminal amino acid is substituted with phenylalanine, leucine, isoleucine, tryptophan, or methionine may also be preferably used as peptides with high HLA-24 binding affinity.
  • peptides in which the second amino acid from the N terminus is substituted with leucine or methionine, and in which C-terminal amino acid is substituted with valine or leucine may be preferably used as peptides with high HLA-0201 binding affinity.
  • one to two amino acids may also be added to the N and/or C terminus of the peptides.
  • the second amino acid from the N terminus is preferably substituted to phenylalanine, tyrosine, methionine, or tryptophan
  • the C-terminal amino acid is preferably substituted to phenylalanine, leucine, isoleucine, tryptophan, or methionine; or one or two amino acids are added to the N terminus and/or C terminus.
  • the present invention provides pharmaceuticals for use in treating tumors or preventing proliferation, metastasis, and such of tumors, where the pharmaceuticals comprise one or more peptides of this disclosure.
  • Angiogenesis at pathologic sites is closely associated with not only tumors, but also with diseases such as diabetic retinopathy, chronic rheumatoid arthritis, psoriasis, and atherosclerosis, and the metastasis of solid tumors ( Folkman, J., Nature Med. 1:27-31 (1995 ); Bicknell, R, Harris, A.L., Curr. Opin. Oncol. 8:60-65 (1996 )). Therefore, the peptides of disclosure can be used to treat tumors, diseases such as diabetic retinopathy, chronic rheumatoid arthritis, psoriasis, atherosclerosis, and metastasis of solid tumors.
  • the peptides used in this invention must have at least a certain level of binding affinity to HLA antigens.
  • the present disclosure provides intracellular vesicles which present complexes formed between the peptides of this invention and HLA antigens on their surface. These intracellular vesicles are called exosomes.
  • Exosomes can be prepared, for example, according to the methods specifically described in Published Japanese Translation of International Publication Nos. Hei 11-510507 and 2000-512161 . Exosomes can preferably be prepared using antigen-presenting cells obtained from subjects who are to be the target of therapy or prophylaxis.
  • the exosomes of this disclosure can be inoculated as cancer vaccines, as for the peptides of this invention.
  • HLA antigens to be used must match that of the subject in need of therapy and/or prophylaxis.
  • HLA-A24 or HLA-A02 particularly HLA-A2402 or HLA-0201, is often appropriate.
  • the present disclosure provides methods for inducing CTLs using the peptides of this disclosure.
  • CTLs are induced in the body of the subject, enhancing immunity against the angiogenic endothelial cells in the tumoral tissues.
  • the methods may be used for ex vivo therapeutic methods, in which subject-derived antigen-presenting cells, CD8-positive cells, or peripheral blood mononuclear leukocytes are contacted (stimulated) in vitro with the peptides of this disclosure to induce CTLs, and then the cells are returned to the subject.
  • the present disclosure provides cytotoxic T cells, that are induced using the peptides of this disclosure and then isolated.
  • the cytotoxic T cells which have been induced by stimulation with antigen-presenting cells that present the peptides of this invention, are preferably derived from subjects to be the target of therapy and/or prophylaxis.
  • the cytotoxic T cells can be administered alone or, for the purpose of antitumor effect, in combination with other drugs, including the peptides, exosomes and so on of this disclosure.
  • the obtained cytotoxic T cells act specifically against target cells presenting the peptides of this disclosure, or preferably, against target cells presenting the same peptides used for induction.
  • the target cells may be cells that endogenously express KDR, or cells forced to express KDR
  • cells that present the peptides of this disclosure on their cell surface due to stimulation by these peptides can also be targeted.
  • the present disclosure also provides antigen-presenting cells that present complexes formed between HLA antigens and the peptides of this disclosure.
  • the antigen-presenting cells that are obtained by contact with the peptides of this disclosure, or with nucleotides encoding the peptides of this disclosure, are preferably derived from subjects to be targeted for therapy and/or prophylaxis.
  • the antigen-presenting cells can be administered as vaccines alone, or in combination with other drugs such as the peptides of this disclosure, exosomes, and cytotoxic T cells.
  • CE652 (SEQ ID NO: 25) refers to one of the epitopes of tumor antigen CEA (carcinoembryonic antigen) that has been reported by Nukaya, 1. (Int. J. Cancer 80, 1999). HIV peptides (ILKEPVHGV (SEQ ID NO: 55) and RYLRDQQLL (SEQ ID NO: 56)) were used as the negative control peptides.
  • the peptides were synthesized according to standard solid-phase synthesis methods using Cleaved PepSet (Mimotope, San Diego, CA), and purified by reverse phase HPLC. The purity (>95%) and the type of peptide were individually determined using HPLC and mass spectrometry.
  • Epstein-Barr virus (EBV)-immortalized B cell lines TISI (HLA-A24/24) and EHM (HLA-A3/3), were provided by Takara Shuzo Biotechnology Research Laboratory.
  • PBMCs peripheral blood mononuclear lymphocytes
  • the obtained PBMCs were left to stand for ten hours in a culture flask (Coming, 43072). After removing the suspended cells, the cells that adhered to the flask were cultured in AIM-V medium (Invitrogen) supplemented with 2% autoserum by adding 1,000 U/mL of human GM-CSF (provided by Kirin Brewery), and 1,000 U/mL of human IL-4 (Genzyme). Five days later, the cells were cultured for another 48 hours in 10 ⁇ g/mL of OK-432 (provided by Chugai Pharmaceutical Co., Ltd.), and were used as antigen-presenting cells for CTL induction.
  • AIM-V medium Invitrogen
  • human GM-CSF provided by Kirin Brewery
  • human IL-4 Human IL-4
  • Pre-induced DCs were pulsed for four hours at 20°C with twelve kinds of 9-mer peptides (SEQ ID NOs: 1 to 12) (20 ⁇ .g/mL), that were predicted in Example 1 to have high binding affinity, in the presence of 3 ⁇ g/mL of ⁇ 2-microglobulin.
  • the resulting DCs were mixed with CD8-positive cells selected by magnetic beads (Dynabeads M-450 and Detachabeads) from PBMC, at a ratio of 1:20 or 1:2, and then cultured in a 48-well plate (Coming), in the presence of 10 ng/mL of human IL-7 (Genzyme).
  • CTL lines established in Example 2 were diluted to 0.3, 1, or 3 cells/well in a U-shaped 96-well plate. 7 x 10 4 cells/well of allo-PBMC, 1 x 10 4 cells/well of EHM, 30 ng/mL of anti-CD3 antibody, and 125 U/mL of IL-2 were added to each well, and AIM-V supplemented with 5% autoserum was added thereto, so that total concentration was 150 ⁇ L/well. Ten days later, 50 ⁇ L/well of IL-2-supplemented medium adjusted was added to a final IL-2 concentration of 125 U/mL. CTLs were functionally analyzed on the 14th day, and CTLs with activity were cultured on a large scale.
  • C53-169 derived from the nonapeptide of SEQ ID NO: 8 (amino acid initiation position KDR169) showed the strongest cytotoxicity.
  • CTLs were induced by a vaccination method, using the 16 types of 9-mer and 10-mer peptides (SEQ ID NO: 26 to 41) predicted in Example 6 on transgenic mice that express human HLA (A0201) ( Hum. Immunol. 2000 Aug.;61(8):764-79 Related Articles, Books, Linkout Induction of CTL response by a minimal epitope vaccine in HLAA*0201/DR1 transgenic mice: dependence on HLA class II restricted T(H) response., BenMohamed L., Krishnan R., Longmate J., Auge C., Low L., Primus J., and Diamond DJ. ).
  • Bone marrow was collected from mouse femur and tibia, and lymphocytes and granulocytes were removed using anti-CD4, CD8, Gr-1 antibodies (Beckton-Dickinson), anti-B220 antibody (Bioscience) and rabbit complement (PeL-Freez). The obtained cells were cultured in a 6-well plate. Suspended cells were collected the following day to culture in RPMI1640 (Invitrogen) medium supplemented with 10% FBS in another 6-well plate, to which 1,000 U/mL of mouse GM-CSF (provided by Kirin Brewery) and 1,000 U/mL of mouse IL-4 (PEPRO TECH) were added.
  • RPMI1640 Invitrogen
  • KDR expression was analyzed by RT-PCR, as indicated in Fig. 3 , to confirm that KDR was not expressed in Colon 26 cells alone, but expressed in the tumoral tissues of mice inoculated with Colon 26. More specifically, tumor vessels were confirmed to appear in tumoral tissues, and to form the tumor.
  • Bone marrow was collected from six- to eight-week old male A2/Kb transgenic mice (TGM) expressing human HLA-A0201.
  • TGM GM-CSF
  • IL-4 Gene
  • the dendritic cells were pulsed with the peptide of SEQ ID NO: 30 (amino acid initiation position KDR773), and administered (1x 10 6 cells/mouse) twice to the left lower quadrant of twelve A2/Kb transgenic mice, with an interval of seven days.
  • B16 melanoma cells ATCC were inoculated (1x 10 6 cells) to the right abdomen of the mice, and mice survival and tumor growth were examined.
  • the peptide of SEQ ID NO: 54 (KDR773-2L), in which the second peptide of SEQ ID NO: 30 is converted to leucine, was added to HLA-A0201-positive T2 strain to produce target cells. Using these cells, the cytotoxic effect of the CTL clone (KDR C44-773-2L (KWC44-773-2L)) obtained from the peptide of SEQ ID NO: 34 in Example 13 was examined by chromium release assay. Fig. 13 shows the results.
  • CTL clone KWC72-772 showed remarkably high cytotoxic effect against HLA-A0201-positive cells presenting KDR peptides on their surface, as compared to activity against cells presenting the EGFP peptide.
  • Example 22 the angiogenesis inhibitory activity of peptide epitopes against the angiogenic response induced by Colon 26 cells in BALB/c mice was evaluated by DAS assay.
  • peptide-specific CTLs were detected in PBMC.
  • PBMC collected from patients (1x 10 5 cells) were incubated with 10 ⁇ M of each peptide in a U-shaped bottom 96-well plate comprising 200 ⁇ L medium.
  • the medium consisted of 45% RPMI1640 medium, 45% AIM-V medium, 10% FBS, 100 U/mL interleukin-2 (IL-2), and 0.1 ⁇ M MEM non-essential amino acid solution. Every three days, half of the medium was removed and replaced with fresh medium containing the corresponding peptide (20 ⁇ M).
  • the present invention provides peptides for use in treating or preventing tumor, which induce cytotoxic T cells by targeting the endothelial cells formed in a wide range of tumoral tissues, and which are extremely effective as cancer vaccines.
  • the present invention also provides pharmaceuticals for treating and preventing tumors, where the pharmaceuticals comprise these peptides.

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Claims (6)

  1. Nonapeptide ou décapeptide choisi parmi les peptides consistant en la séquence d'acides aminés de SEQ ID NO : 30, 29, 33, 34, 40, 46 ou 54 pour une utilisation dans le traitement ou la prévention de tumeur.
  2. Nonapeptide choisi parmi les peptides consistant en la séquence d'acides aminés de SEQ ID NO : 2, 3, 5, 11 ou 12 pour une utilisation dans le traitement ou la prévention de tumeur.
  3. Composition pharmaceutique pour une utilisation dans le traitement et/ou la prévention de tumeurs, dans laquelle la composition pharmaceutique comprend un ou plusieurs peptides définis dans la revendication 1 ou 2.
  4. Vaccin pour une utilisation dans le traitement ou la prévention de tumeur, dans lequel le vaccin comprend un peptide défini dans la revendication 1 ou 2 comme un ingrédient actif.
  5. Vaccin selon la revendication 4 pour une utilisation dans le traitement ou la prévention de tumeur qui est utilisé pour une administration à un sujet dont l'antigène HLA est HLA-A02 ou HLA-A24.
  6. Vaccin selon la revendication 4 ou 5 pour une utilisation dans le traitement ou la prévention de tumeur qui est utilisé pour réprimer la croissance et/ou les métastases des tumeurs malignes.
EP08018875A 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant Expired - Lifetime EP2014678B1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP10010176.5A EP2270042B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010172.4A EP2261248B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010173.2A EP2261249B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
DK10010174.0T DK2267022T3 (en) 2002-09-12 2003-09-12 KDR peptides and vaccines comprising the same
DK10010175.7T DK2267023T3 (en) 2002-09-12 2003-09-12 KDR peptides and vaccines comprising the same
EP10010170.8A EP2270041B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010169.0A EP2267021B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
DK10010173.2T DK2261249T3 (en) 2002-09-12 2003-09-12 KDR peptides and vaccines comprising the same
EP10010175.7A EP2267023B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010171A EP2261247A3 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010174.0A EP2267022B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
DK10010169.0T DK2267021T3 (en) 2002-09-12 2003-09-12 KDR peptides and vaccines comprising the same
CY20121100072T CY1113379T1 (el) 2002-09-12 2012-01-19 Πεπτιδια κdr και εμβολια που τα περιλαμβανουν

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2002267285 2002-09-12
JP2003062003 2003-03-07
JP2003167042 2003-06-11
EP03795432A EP1548032B9 (fr) 2002-09-12 2003-09-12 Peptides kdr et vaccins les renfermant

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP03795432.8 Division 2003-09-12
EP03795432A Division EP1548032B9 (fr) 2002-09-12 2003-09-12 Peptides kdr et vaccins les renfermant

Related Child Applications (15)

Application Number Title Priority Date Filing Date
EP10010173.2A Division EP2261249B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010169.0A Division EP2267021B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010176.5A Division EP2270042B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010175.7A Division EP2267023B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010170.8A Division EP2270041B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010174.0A Division EP2267022B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010172.4A Division EP2261248B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010170.8 Division-Into 2010-09-22
EP10010176.5 Division-Into 2010-09-22
EP10010171.6 Division-Into 2010-09-22
EP10010174.0 Division-Into 2010-09-22
EP10010175.7 Division-Into 2010-09-22
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EP08018897A Expired - Lifetime EP2014679B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les renfermant
EP10010170.8A Expired - Lifetime EP2270041B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010175.7A Expired - Lifetime EP2267023B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP08018875A Expired - Lifetime EP2014678B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010171A Withdrawn EP2261247A3 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP10010172.4A Expired - Lifetime EP2261248B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
EP03795432A Expired - Lifetime EP1548032B9 (fr) 2002-09-12 2003-09-12 Peptides kdr et vaccins les renfermant
EP10010173.2A Expired - Lifetime EP2261249B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
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EP08018897A Expired - Lifetime EP2014679B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les renfermant
EP10010170.8A Expired - Lifetime EP2270041B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
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EP03795432A Expired - Lifetime EP1548032B9 (fr) 2002-09-12 2003-09-12 Peptides kdr et vaccins les renfermant
EP10010173.2A Expired - Lifetime EP2261249B1 (fr) 2002-09-12 2003-09-12 Peptides KDR et vaccins les comportant
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HK1151032A1 (en) 2012-01-20
US7514084B2 (en) 2009-04-07
EP1548032B9 (fr) 2009-10-28
US7695720B2 (en) 2010-04-13
SI2014678T1 (sl) 2012-03-30
DK2267022T3 (en) 2015-02-23
EP2261248B1 (fr) 2015-02-18
ATE531729T1 (de) 2011-11-15
EP2014679A1 (fr) 2009-01-14
JP3971769B2 (ja) 2007-09-05
US20120328636A1 (en) 2012-12-27
EP2267022A2 (fr) 2010-12-29
US20060216301A1 (en) 2006-09-28
EP2261247A3 (fr) 2011-02-16
DK1548032T3 (da) 2009-08-17
HK1125659A1 (en) 2009-08-14
JP4185143B2 (ja) 2008-11-26
DE60327786D1 (de) 2009-07-09
EP2261249A3 (fr) 2011-02-16
US20100215676A1 (en) 2010-08-26
EP2267023B1 (fr) 2015-02-11
US8574586B2 (en) 2013-11-05
DK2261249T3 (en) 2015-02-16
JPWO2004024766A1 (ja) 2006-01-26
PT2014678E (pt) 2012-01-05
EP2270041A3 (fr) 2011-02-16
CN101139392B (zh) 2012-12-26
EP1548032B1 (fr) 2009-05-27
HK1151039A1 (en) 2012-01-20
EP2267022B1 (fr) 2015-02-11
EP2270042A3 (fr) 2011-02-16
CN103073620B (zh) 2014-12-10
JP2007191485A (ja) 2007-08-02
EP1548032A1 (fr) 2005-06-29
EP2261249A2 (fr) 2010-12-15
CY1113379T1 (el) 2016-06-22
EP2014679B1 (fr) 2010-05-05
EP2014678A3 (fr) 2009-03-25
CN101139393A (zh) 2008-03-12
EP2261249B1 (fr) 2015-02-11
CN103073620A (zh) 2013-05-01
AU2003264419A1 (en) 2004-04-30
US8206719B2 (en) 2012-06-26
US20090252752A1 (en) 2009-10-08
EP2267021A3 (fr) 2011-02-16
EP2267021B1 (fr) 2015-02-18
EP1548032A4 (fr) 2006-03-01
JP2007277251A (ja) 2007-10-25
HK1151037A1 (en) 2012-01-20
EP2014678A2 (fr) 2009-01-14
EP2261248A2 (fr) 2010-12-15
US8574585B2 (en) 2013-11-05
HK1151036A1 (en) 2012-01-20
EP2270042B1 (fr) 2015-01-14
EP2267023A2 (fr) 2010-12-29
EP2267021A2 (fr) 2010-12-29
EP2270042A2 (fr) 2011-01-05
CN101139392A (zh) 2008-03-12
EP2261248A3 (fr) 2011-02-16
CN100352843C (zh) 2007-12-05
US20130028923A1 (en) 2013-01-31
DK2267021T3 (en) 2015-03-30
EP2267022A3 (fr) 2011-02-16
EP2270041A2 (fr) 2011-01-05
ATE432291T1 (de) 2009-06-15
EP2267023A3 (fr) 2011-02-16
HK1151038A1 (en) 2012-01-20
SI1548032T1 (sl) 2009-10-31
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PT1548032E (pt) 2009-08-13
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EP2261247A2 (fr) 2010-12-15
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CN103951745A (zh) 2014-07-30
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CN1694901A (zh) 2005-11-09
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HK1151035A (en) Kdr peptides and vaccines comprising the same

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